Far beyond declarative and non-declarative memories

International audienceAccording to general learning theory two major forms of learning can be observed across species. These universal forms of learning are classical and operant conditioning (Tarpy, 1997). Although both forms of conditioning can occur in the absence of awareness of the contingencies between CS (conditioned stimulus) and UCS (unconditioned stimulus) (or action – consequence contingencies) (Huston and Oitzl, 1989; Clark and Squire, 1998), close temporal proximity between a CS and a UCS is required to form an association. In other words, long-term association between a CS and a UCS (or an operant and its consequence) requires two distinct events to occur simultaneously or with little delay (in the range of ms) between them

The role of KIBRA in reconstructive episodic memory

In order to retrieve episodic past events, the missing information needs to be reconstructed using information stored in semantic memory. Failures in these reconstructive processes are expressed as false memories. KIBRA single nucleotide polymorphism (rs17070145) has been linked to episodic memory performance as well as an increased risk of Alzheimer’s disease and post-traumatic stress disorder (PTSD). Here, the role of KIBRA rs17070145 polymorphism (male and female CC vs. CT/TT carriers) in reconstructive episodic memory in the Deese-Roediger-McDermott (DRM) paradigm was investigated in N = 219 healthy individuals. Female participants outperformed males in the free recall condition. Furthermore, a trend towards a gender x genotype interaction was found for false recognition rates. Female CT/TT carriers exhibited a lower proportion of false recognition rates for associated critical lures as compared to male CT/TT. Additionally, an association between KIBRA rs17070145 genotype, familiarity and recollection based recognition performance was found. In trials with correct recognition of listed items CT/TT carriers showed more “remember”, but fewer “know” responses as compared to CC carriers. Our findings suggest that the T-allele of KIBRA rs17070145 supports recollection based episodic memory retrieval and contributes to memory accuracy in a gender dependent manner. Findings are discussed in the context of the specific contribution of KIBRA related SNPs to reconstructive episodic memory and its implications for cognitive and emotional symptoms in dementia and PTS

Effects of appraisal training on responses to a distressing autobiographical event

Dysfunctional appraisals are a key factor suggested to be involved in the development and maintenance of PTSD. Research has shown that experimental induction of a positive or negative appraisal style following a laboratory stressor affects analogue posttraumatic stress symptoms. This supports a causal role of appraisal in the development of traumatic stress symptoms and the therapeutic promise of modifying appraisals to reduce PTSD symptoms. The present study aimed to extend previous findings by investigating the effects of experimentally induced appraisals on reactions to a naturally occurring analogue trauma and by examining effects on both explicit and implicit appraisals. Participants who had experienced a distressing life event were asked to imagine themselves in the most distressing moment of that event and then received either a positive or negative Cognitive Bias Modification training targeting appraisals (CBM-App). The CBM-App training induced training-congruent appraisals, but group differences in changes in appraisal over training were only seen for explicit and not implicit appraisals. However, participants trained positively reported less intrusion distress over the subsequent week than those trained negatively, and lower levels of overall posttraumatic stress symptoms. These data support the causal relationship between appraisals and trauma distress, and further illuminate the mechanisms linking the two

Investigating the effect of proactive interference control training on intrusive memories = Investigando el efecto del entrenamiento de control de interferencias proactivas en las memorias intrusivas = 研究主动干扰控制训练对闯入性记忆的影响

Intrusive re-experiencing is a hallmark symptom of Posttraumatic Stress Disorder (PTSD). According to prominent models of intrusive phenomena, intrusive memories may result from impairments in the efficiency of working memory capacity (WMC), more specifically proactive interference control. Yet, experimental research is scarce. Therefore, the present study aimed to investigate experimentally the role of proactive interference control in intrusive memories. We randomly assigned 57 healthy participants to either receive a high interference control training or a low interference control training. Participants were then exposed to highly distressing film clips. WMC was assessed before and after the training. Intrusion symptoms were assessed directly post-training and after one week using an Intrusion Provocation Task (IPT), a one-week intrusions diary, and the retrospective intrusion subscale of the Impact of Event Sale – Revised (IES-R). Results indicated that both groups reported improvements in WMC and fewer intrusions on the second IPT post-training, with no differences between groups. Similarly, no group differences on intrusions were found at one-week follow-up (i.e., intrusion diary and IES-R). To conclude, these data are not consistent with the hypothesis that WMC plays a role in intrusive re-experiencing. Implications for future research are discussed. / La re-experiencia intrusiva es un síntoma distintivo del trastorno por estrés postraumático (TEPT). De acuerdo con los prominentes modelos de fenómenos intrusivos, las memorias intrusivas pueden resultar en deterioros en la eficiencia de la capacidad de memoria de trabajo (CMT), más específicamente del control proactivo de interferencias. Sin embargo, la investigación experimental a este respecto es escasa. Por lo tanto, el presente estudio tuvo como objetivo investigar experimentalmente el papel del control proactivo de interferencias en las memorias intrusivas. Asignamos aleatoriamente 57 participantes sanos a recibir, ya sea, un entrenamiento de control de alta interferencia o un entrenamiento de control de baja interferencia. Luego, los participantes fueron expuestos a videoclips de películas altamente angustiantes. La CMT fue evaluada antes y después del entrenamiento. Los síntomas de intrusión se evaluaron directamente después del entrenamiento y después de una semana utilizando una Tarea de Provocación de Intrusión (IPT), registro diario de intrusiones (por una semana), y la subescala de intrusión retrospectiva de la Escala del Impacto del Evento - Revisada (IES-R). Los resultados indicaron que ambos grupos experimentaron mejoras en la CMT y reducción de intrusiones en la segunda IPT posterior al entrenamiento, sin diferencias entre los grupos. De manera similar, no se encontraron diferencias de grupo en las intrusiones en el seguimiento de una semana (es decir, en el diario de intrusiones y la IES-R). Para concluir, estos datos no son consistentes con la hipótesis de que la CMT desempeña un papel en la re-experiencia intrusiva. Se discuten las implicaciones para futuras investigaciones. / 闯入性再体验是创伤后应激障碍（PTSD）的标志性症状。根据闯入现象的经典模型，闯入性记忆可能是由工作记忆容量（WMC）效率的损害引起的，更具体地说是主动干扰控制。然而，这方面实验研究很少。因此，本研究通过实验研究主动干扰控制在闯入性记忆中的作用。我们随机分配了57名健康被试，以接受高干扰控制训练或低干扰控制训练。然后被试接触到令人非常痛苦的电影片段。在训练前后对WMC进行了评估。在训练后和一周后随访使用闯入激发任务（IPT），一周闯入症状日记以及事件影响量表修订版（IES－R）的回顾性闯入子量表直接评估闯入症状。结果表明，两组均报告WMC改善，第二次IPT训练后闯入较少，两组间无差异。同样，在一周的随访中没有发现闯入的群体差异（即闯入日记和IES-R）。总之，这些数据与WMC在闯入性再体验中发挥作用的假设不一致。文中讨论了对未来研究的启示

Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H1, H2 and H3 receptors

Histamine is a transmitter that activates the four receptors H1R to H4R. The H3R is found in the nervous system as an auto and heteroreceptor, and controls the release of neurotransmitters, making it a potential drug target for neuropsychiatric conditions. We have previously reported that the 1?(2,3?dihydro?1?benzofuran?2?yl)methylpiperazines (LINS01 compounds) have selectivity for the H3R over the H4R. Here we describe their pharmacological properties at the human H1R, H2R in parallel with the H3R, thus providing a full analysis of these compounds as histamine receptor ligands through reporter gene assays. Eight of the nine LINS01 compounds inhibited H3R?induced histamine responses but no inhibition of H2R?induced responses were seen. Three compounds were weakly able to inhibit H1R?induced responses. No agonist responses were seen to any of the compounds at any receptor. SAR analysis shows that the N?methyl group improves H3R affinity whilst the N?phenyl group is detrimental. The methoxy derivative, LINS01009, had the highest affinity

The dopamine D2 receptor mediates approach-avoidance tendencies in smokers

Dopamine D2 receptors (DRD2) have been strongly implicated in reward processing of natural stimuli and drugs. By using the Approach-Avoidance Task (AAT), we recently demonstrated that smokers show an increased approach bias toward smoking-related cues but not toward naturally-rewarding stimuli. Here we examined the contribution of the DRD2 Taq1B polymorphism to smokers’ and non-smokers’ responsivity toward smoking versus naturally-rewarding stimuli in the AAT. Smokers carrying the minor B1 allele of the DRD2 Taq1B polymorphism showed reduced approach behavior for food-related pictures compared to non-smokers with the same allele. In the group of smokers, a higher approach-bias toward smoking-related compared to food-related pictures was found in carriers of the B1 allele. This pattern was not evident in smokers homozygous for the B2 allele. Additionally, smokers with the B1 allele reported fewer attempts to quit smoking relative to smokers homozygous for the B2 allele. This is the first study demonstrating that behavioral shifts in response to smoking relative to natural rewards in smokers are mediated by the DRD2 Taq1B polymorphism. Our results indicate a reduced natural-reward brain reactivity in smokers with a genetically determined decrease in dopaminergic activity (i.e., reduction of DRD2 availability). It remains to be determined whether this pattern might be related to a different outcome after psychological cessation interventions, i.e. AAT modification paradigms, in smokers

Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans

Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher–like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue

Astrocytic transporters in Alzheimer's disease

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer’s disease. These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease modifying therapies for Alzheimer’s disease, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of Alzheimer’s disease. A small number of the four hundred transporter superfamilies’ are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in Alzheimer’s disease. Here we review the current evidence for six astrocytic transporter subfamilies involved in Alzheimer’s disease, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling Alzheimer’s disease